Cyclophilin D-Sensitive Mitochondrial Permeability Transition in Adult Human Brain and Liver Mitochondria
Cyclophilin D-Sensitive Mitochondrial Permeability Transition in Adult Human Brain and Liver Mitochondria
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DOI：
10.1089/neu.2010.1613
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发表时间：
2011-01-01
影响因子：
4.2
通讯作者：
Elmer, Eskil
中科院分区：
文献类型：
--
作者：
Hansson, Magnus J.;Morota, Saori;Elmer, Eskil
线粒体通透性转变（mPT）被认为是中枢神经系统（CNS）和其他器官的多种病理生理条件下细胞死亡的主要原因。基质蛋白亲环蛋白 D (CypD) 的药理学抑制或基因敲除可防止多种脑损伤模型中的 mPT 和细胞变性。如果动物模型中的这些发现可以转化为人类疾病，那么 mPT 的药理学抑制提供了一个有希望的治疗靶点。本研究的目的是验证成人大脑和肝脏线粒体中是否存在 CypD 敏感的 mPT。为了对人类线粒体进行功能表征，在出血或肿瘤手术期间获得新鲜组织样本，并快速分离线粒体。 CypD 抑制剂环孢菌素 A 显着增加了人脑和肝脏线粒体中的线粒体钙保留能力（mPT 的定量测定），而硫醇反应性化合物和氧化剂使线粒体对钙诱导的 mPT 敏感。脑线粒体在钙超载时发生肿胀，而在钙去除后，这种肿胀是可逆的。为了进一步探索人类线粒体的 mPT，肝线粒体被证明表现出 mPT 现象的几个经典特征，例如钙诱导的膜电位损失和呼吸耦合，以及促凋亡蛋白细胞色素 c 的释放。我们得出的结论是，成人活人脑和肝线粒体具有活性的 CypD 敏感 mPT。我们的研究结果支持 CypD 和 mPT 抑制作为急性和慢性神经变性的药理学靶点的基本原理。
The mitochondrial permeability transition (mPT) is considered to be a major cause of cell death under a variety of pathophysiological conditions of the central nervous system (CNS) and other organs. Pharmacological inhibition or genetic knockout of the matrix protein cyclophilin D (CypD) prevents mPT and cell degeneration in several models of brain injury. If these findings in animal models are translatable to human disease, pharmacological inhibition of mPT offers a promising therapeutic target. The objective of this study was to validate the presence of a CypD-sensitive mPT in adult human brain and liver mitochondria. In order to perform functional characterization of human mitochondria, fresh tissue samples were obtained during hemorrhage or tumor surgery and mitochondria were rapidly isolated. Mitochondrial calcium retention capacity, a quantitative assay for mPT, was significantly increased by the CypD inhibitor cyclosporin A in both human brain and liver mitochondria, whereas thiol-reactive compounds and oxidants sensitized mitochondria to calcium-induced mPT. Brain mitochondria underwent swelling upon calcium overload, which was reversible upon calcium removal. To further explore mPT of human mitochondria, liver mitochondria were demonstrated to exhibit several classical features of the mPT phenomenon, such as calcium-induced loss of membrane potential and respiratory coupling, as well as release of the pro-apoptotic protein cytochrome c. We concluded that adult viable human brain and liver mitochondria possess an active CypD-sensitive mPT. Our findings support the rationale of CypD and mPT inhibition as pharmacological targets in acute and chronic neurodegeneration.